search text   Advanced Search

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Kimberly, M. B. Articles by Schreiner, M. Search for Related Content PubMed Articles by Kimberly, M. B. Articles by Schreiner, M. Related Collections Office Practice

Variation in Standards of Research Compensation and Child Assent Practices: A Comparison of 69 Institutional Review Board–Approved Informed Permission and Assent Forms for 3 Multicenter Pediatric Clinical Trials

^a Pediatric Generalist Research Group
^e Center for Research Integrity
^f Children's Clinical Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
^b Center for Bioethics
^d Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania
^c Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
OBJECTIVE. To systematically compare standards for compensation and child participant assent in informed permission, assent, and consent forms (IP-A-CFs) approved by 55 local institutional review boards (IRBs) reviewing 3 standardized multicenter research protocols.

METHOD. Sixty-nine principal investigators participating in any of 3 national, multicenter clinical trials submitted standardized research protocols for their trials to their local IRBs for approval. Copies of the subsequently IRB-approved IP-A-CFs were then forwarded to an academic clinical research organization. This collection of IRB-approved forms allowed for a quasiexperimental retrospective evaluation of the variation in informed permission, assent, and consent standards operationalized by the local IRBs.

RESULTS. Standards for compensation and child participant assent varied substantially across 69 IRB-approved IP-A-CFs. Among the 48 IP-A-CFs offering compensation, monetary compensation was offered by 33 as reimbursement for travel, parking, or food expenses, whereas monetary or material compensation was offered by 22 for subject inconvenience and by 13 for subject time. Compensation ranged widely within and across studies (study 1, $180–1425; study 2, $0–500; and study 3, $0–100). Regarding child participant assent, among the 57 IP-A-CFs that included a form of assent documentation, 33 included a line for assent on the informed permission or consent form, whereas 35 included a separate form written in simplified language. Of the IP-A-CFs that stipulated the documentation of assent, 31 specified 1 age ranges for obtaining assent. Informed permission or consent forms were addressed either to parents or child participants.

CONCLUSION. In response to identical clinical trial protocols, local IRBs generate IP-A-CFs that vary considerably regarding compensation and child participant assent.

Key Words: ethics • institutional review board • permission • assent • informed consent • research subjects • quasiexperimental design

Abbreviations: IRB—institutional review board • IP-A-CF—informed permission, assent, and consent form • CCRI—Children's Clinical Research Institute • PI—principal investigator • AHRF—acute hypoxemic respiratory failure

How do different institutional review boards (IRBs) vary in their application of standards for compensation and child participant assent for identical pediatric clinical trial protocols? The standards and spirit of informed consent, an essential component of ethical conduct of human subjects research,^1–4 are operationalized in pediatric research in 3 distinguishable forms: permission of parents or guardians, assent of child subjects in accord with their developmental level, and consent of emancipated adolescents and young adults.⁵ For each of these forms of permitting, assenting, or consenting to research participation, controversy remains over what constitutes best practices at an operational level of detail.

At a general level, guidance on the proper content and process of informed consent and assent follows from several authoritative sources. Federal regulations promulgated in 1981, and today known as the Common Rule,⁶ require institutions that receive federal funding to use IRBs to review human subjects research proposals and to evaluate and approve informed consent forms. In 1998 the US Food and Drug Administration updated the Guidance for Institutional Review Boards and Clinical Investigators outlining in greater detail its expectations for documentation of informed consent and assent.⁷ In the pediatric research setting, IRBs review a broader set of documents that appropriately correspond with children's developing capacity to make decisions for themselves. These forms document agreement to participate in the research study by the child's guardian's informed permission, the child's assent, or the emancipated minor's or young adult's informed consent. Although the labels affixed to these documents vary, we refer to them collectively as informed permission, assent, and consent forms (IP-A-CFs).

At a detailed level, the exact parameters for meeting the enumerated elements of IP-A-CFs are still left essentially to the discretion of local IRBs. Federal regulations promulgated in 1983 and reiterated by the Food and Drug Administration in 2001 grant IRBs wide discretion to determine whether child assent should be obtained or documented in addition to parental permission.^{8, 9} Unless the research protocol offers the child direct benefit not otherwise available, researchers are required to obtain assent unless the child is not capable. Yet, unlike the informed consent standards, the regulations specify no key elements of assent.⁹

Despite the latitude afforded to IRBs, little research addresses how different IRBs vary in their handling of informed consent and assent. A previous study¹⁰ described variability in IRB chairpersons' opinions about discretionary aspects of child assent and compensation; nonetheless, how chairpersons believe their IRBs should exercise discretion may, in fact, differ from actual IRB behavior. Two other studies^{11, 12} each used a combination of methods to describe variation in the process of local IRB review of protocols and IP-A-CFs, although neither study analyzed IP-A-CFs themselves. Because variation in how IRBs operationalize informed consent and child participant assent has implications regarding the current state of human subject protection, particularly with regard to compensation and assent, we conducted a retrospective systematic evaluation of IP-A-CFs generated by local IRBs at different sites in response to the same multicenter clinical research protocols.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Design
We performed a retrospective quasiexperimental study in which multiple local IRBs were exposed to identical study protocols, so that variation in IRB-approved forms indicate variation in IRB standards as opposed to variation in study design. Three pharmaceutical companies each independently contracted with the Children's Clinical Research Institute (CCRI), an academic clinical research organization located at the Children's Hospital of Philadelphia, to oversee the conduct of 3 national, phase III, multicenter clinical trials conducted for 3 pharmaceutical products. For each of the 3 clinical trials, CCRI solicited principal investigators (PIs) at sites across the country, sending those who agreed to participate the standardized research protocols and template IP-A-CFs. PIs submitted the research protocols and forms to their IRBs for approval. After PIs made the alterations required by their local IRBs, they each returned a copy of their IRB-approved IP-A-CFs back to CCRI for approval and for record keeping. This collection of IRB-approved forms allowed for a quasiexperimental retrospective review of informed consent and assent standards for each of the 3 clinical trials across multiple sites.

Subjects and Setting
In total, 55 different IRBs in 23 states, the District of Columbia, and Puerto Rico were exposed to 69 research protocol submissions divided among 3 different multi-institutional pediatric randomized, placebo-controlled clinical trials.

Trial Study Protocols
The hypertension study (n = 36 submissions) was a dose-escalation, randomized, withdrawal trial. Children with hypertension who responded to high dose medication were randomized to either placebo or low-, medium-, or high-dose ramipril. The pain study (n = 14 submissions) randomized children with breakthrough cancer pain to either oral transmucosal fentanyl citrate or placebo (with rapid availability of active rescue medication if needed for pain) after a dose-finding and pharmacokinetic phase. The acute hypoxemic respiratory failure (AHRF) study (n = 19 submissions) randomized children to either inhaled nitric oxide or placebo as an adjunct to standard treatment for severe acute lung injury.

Analysis
Data were abstracted using a standard spreadsheet and included site-specific requirements for compensation and assent. Data were abstracted and cross-validated by 2 investigators (MBK and KSH).

Our unit of analysis was the discrete protocol submission and review that yielded 69 IP-A-CFs. We did not study the 55 IRBs per se, because variability of standards within a given IRB for the same study precluded a clear classification of specific IRBs regarding their standards (eg, 1 IRB approved different levels of compensation for 2 different PIs using the same protocol). The data from all 69 of the IP-A-CFs were analyzed using simple descriptive statistics of proportions.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
In our sample of 69 protocol submissions, IRBs demonstrated substantial variability in how they operationally defined the key elements of compensation and assent (Tables 1 and 2).

View larger version (9K): [in this window] [in a new window]   FIGURE 1 Range in compensation for each of 3 multisite clinical trials. Hypertension study ranged nearly eightfold from least to greatest compensation level.

Assent
Overall, 57 IP-A-CFs (83%) included some method for documenting child participant assent (Table 2). Although children eligible for participation in the AHRF study were all seriously ill and required mechanical ventilation, 11 IP-A-CFs (58%) for the AHRF study included a mechanism for documenting assent. Of the 57 IP-A-CFs with assent documentation, 21 (37%) documented assent with only an assent signature line for the child on the parental permission form itself, whereas 36 (63%) included assent forms separate from the permission forms. Of those that included a separate assent form(s), 1 (2%) included a single separate assent form that used the same language as the permission form; 17 (30%) used a single separate assent form written in age-adjusted language; 12 (21%) used a line on the permission form in addition to a single separate assent form written in age-adjusted language for different age-ranges of potential participants; and 6 (10%) used multiple separate assent forms with differentially simplified language for different age ranges of potential participants. Of the 57 IP-A-CFs that included some method for documenting assent, 31 (54%) stipulated specific but variable age ranges for providing assent (Fig 2). Only 5 IP-A-CFs (7%) overall provided a means of documenting a waiver of assent, 2 of which where in the AHRF study. Of the self-titled "informed consent forms," 45 (65%) were addressed to the parents or guardians of the potential child participants, whereas the remaining 24 (35%) were addressed to the potential participants themselves despite their lack of standing to consent.

View larger version (34K): [in this window] [in a new window]   FIGURE 2 The explicitly stated age range for documentation of assent varied considerably across IRB-approved IP-A-CFs. Bars represent inclusive age ranges corresponding to each IP-A-CF with an explicitly stated age range(s); the first vertical bar, extending from age 7 to age 14, indicates a specified range of age 7 through age 13, or from the 7th birthday to the day before the 14th birthday. A break in a bar indicates that the overall specified age range was divided into 2 separate age ranges with 2 different forms of documentation.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

Compensation
Compensation ranged widely among institutions within the same multicenter trials, as well as among the different multicenter trials. Indeed, given the eightfold difference in compensation stated among the hypertension study IP-A-CFs, some IRBs may be either undercompensating or overcompensating participants.

Compensation for participation in research falls into 2 categories. First, compensation may aim to diminish financial disincentives to participation by reimbursing participants travel expenses and lost time, a practice that is generally viewed as ethically appropriate.^{13, 14} Among the 48 IP-A-CFs offering compensation, 33 (69%) offered reimbursement for travel and food expenses; 5 (10%) of those 33 reimbursed only documented expenses that the participants had incurred, whereas the remainder offered a fix sum to cover estimated expenses (with the possibility of slight underpayment or overpayment unlikely to influence the decision regarding whether to participate; ref 15). Second, compensation may aim to motivate participation, either by expressing appreciation with a token gift (that is, an item of trivial value, such as a t-shirt, stuffed animal, or small gift certificate) or more forthrightly attempting to induce participants to accept the burdens of participation by paying them.¹⁶ The impact of various compensation schemes on research participation warrants further empirical investigation. Across the spectrum of compensation, ranging from approaches that fail to reimburse the full amount of participant out-of-pocket expenses through to approaches that provide participants with payment well beyond the reimbursement of incurred expenses, these schemes may adversely affect research study access and participation decisions, especially for financially disadvantaged potential subjects.

More investigation is also called for to understand the sources of the many variations in compensation discovered in our study. For instance, among the hypertension study sites, the specified compensation (when divided by the time required to participate) ranged from $7.50 to nearly $60 an hour, resulting in a difference in total compensation of more than $1200. Compensation also varied importantly across different studies: the pain study required participants to assume the burdens of hospitalization and additional travel, lodging, and meal expenses, but only 6 IP-A-CFs (43%) offered families compensation. By contrast, participants in the AHRF trial were already hospitalized with central lines, yet 6 IP-A-CFs (32%) offered compensation for participation, although there was virtually no extra financial burden.

Excessive variability in compensation may be because of the discretion afforded IRBs by federal regulations. Although codifying strict methodologies to determine precise and inflexible levels of compensation would be incompatible with the need to tailor compensation standards to local population characteristics and even individual family characteristics, the unlimited latitude that IRBs can exercise in approving participant compensation likely promotes excessive variability. No data were available to determine whether the variability in our study flowed from differences in opinion with regard to appropriateness of reimbursement payments, incentive payments, or both forms of payment. Additional empirical work is necessary to determine which factors generate this variability and to what extent and to characterize the standards that IRBs use when approving compensation amounts, whether explicitly or implicitly.

Finally, despite recent guidance by the Institute of Medicine to clearly disclose the recipient of payments,¹⁶ we found that, among IP-A-CFs offering compensation, most (25 [52%]) were ambiguous about to whom the compensation was offered. When they were specific, compensation was offered with about equal frequency to parents (6 [13%]), to children (8 [17%]), or to both (9 [19%]). The impact of either ambiguity regarding who receives the compensation or explicit specification of these different recipients should be studied with regard to both willingness of participation and voluntariness of permission or assent.

Child Participant Assent
Among the documents examined in this study, IRBs exhibited substantially different standards for requiring and documenting children's assent to participate in research. Of the 69 IP-A-CFs reviewed in this study, 57 (83%) included methods for documenting assent, and, among those, 31 (54%) stipulated age ranges for obtaining assent. Despite the 1978 recommendation by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research that assent be obtained from all children 7 years of age,¹ the age ranges specified in the IP-A-CFs spanned from a lower limit of 7–13 to an upper limit of 15–18 and were often (13 of 31) divided into 2 sequential age ranges, each regarding a different mode of documentation.

The interpretation of these data regarding the age range of assent specified in the IP-A-CFs is subject to 2 primary limitations. First, the absence of a stipulated age range on an assent form does not necessarily indicate that a given IRB does not have a standing policy that specifies an age range for attempting to obtain assent across all research protocols. Second, the specification of an assent age range in a IP-A-CF document may not necessarily imply that assent must be obtained but rather that a good-faith attempt to obtain assent must be undertaken. However, even with these caveats in mind, the presence of stipulated age ranges for obtaining assent are good indications that a given IRB intends investigators to obtain assent in the indicated manner and, at a minimum, provide an important nuance to the interpretation of a previous survey finding¹⁰ that 89% of IRB chairpersons support the use of stipulated age-cutoffs for categorically determining which children are capable of assent.

Different definitions of assent may explain much of the variation among IP-A-CFs regarding age ranges for documentation of assent. Some definitions formulate assent as a form of consent, in which case it is important that the assenting child understand the risks and benefits of participation. The elements of assent, defined in this way, are similar to those of informed consent itself, and most IRBs self-consciously rely on regulations for informed consent forms when approving the content of assent forms.¹⁰ Other definitions of assent emphasize the process of gauging the child's preference, indifference, or disinclination to participate in a study that may require additional needle pricks or an extra hour in the hospital. Given this definition of assent, a child's cognitive ability to understand and process the risks and benefits of participation is not important, and so children of a younger age are capable of assenting. The differences between these 2 definitions may explain why 1 IP-A-CF required assent for ages 15–18, for instance, whereas another required it for ages 7–13.

As with participant compensation, further research is needed to clarify the sources of variation regarding assent procedures. For instance, some informed permission and consent forms were addressed to the child participants (35%) and some to their parents (65%). This may simply represent the writing style preference of each IRB or perhaps a desire to express respect for the developing autonomy of older children or adolescent participants. Yet, because informed consent for children is legally conducted by proxy by their parents or guardians as informed permission and because, when they are capable, children should be offered an opportunity to assent independent of the full informed consent form, addressing the informed permission and consent forms of pediatric protocols with children incapable of consent may only generate confusion about who has the authority to make participation decisions and about the role and importance that age-appropriate child assent plays in the research process.

Assent practices should also be clarified at the operational level with respect to what constitutes a good faith effort to obtain a child's assent and when assent can be waived. The participants eligible for the AHRP study, for instance, were seriously ill with a life-threatening condition (all required mechanical ventilation and most were likely to be nonresponsive because of either their underlying illness or analgesic medications), yet 11 (58%) of the 19 IP-A-CFs in this study included documentation of assent, whereas only 2 (10%) included documentation of waiver of assent.

	CONCLUSIONS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Federal regulations implicitly grant IRBs significant discretion for documentation of informed consent for human subjects of research. Our sample of 69 sets of IP-A-CFs addressing 3 multicenter randomized, clinical trials reveals substantial variability in compensation and assent standards among IRBs across the country.

	FOOTNOTES

 
Accepted Nov 2, 2005.

Address correspondence to Michael Kimberly, MBe, 597 Orange St, New Haven, CT 06511. E-mail: mbk{at}alumni.princeton.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

1. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, DC: US Government Print Office; 1978
2. Annas GJ, Grodin MA. The Nazi Doctors and the Nuremberg Code: Human Rights in Human Experimentation. New York, NY: Oxford University Press; 1992
3. Faden RR, Beauchamp TL, King NMP. A History and Theory of Informed Consent. New York, NY: Oxford University Press; 1986
4. Levine RJ. Ethics and Regulation of Clinical Research. 2nd ed. Baltimore, MD: Urban & Schwarzenberg; 1986
5. Committee on Bioethics. Informed consent, parental permission, and assent in pediatric practice. Committee on Bioethics, American Academy of Pediatrics. Pediatrics. 1995;95 :314 –317[Abstract/Free Full Text]
6. Code of Federal Regulations. 45 CFR 46:116–117. Federal Policy for the Protection of Human Subjects (Subpart A). Washington, DC: United States Department of Health and Human Services; 1991
7. US Food and Drug Administration. Information Sheets: Guidance for Institutional Review Boards and Clinical Investigators. 1998 Update. Available at: www.fda.gov/oc/ohrt/irbs/default.htm. Accessed October 30, 2005
8. US Department of Health and Human Services. 45 CFR Part 46: additional protections for children involved as subjects in research (hereafter "subpart D"). Fed Regist. 1983;48 :9814 –9820[Medline]
9. Food and Drug Administration, US Department of Health and Human Services. 21 CFR Parts 50 and 56: additional safeguards for children in clinical investigations of FDA regulated products. Fed Regist. 2001;66 :20589 –20600
10. Whittle A, Shah S, Wilfond B, Gensler G, Wendler D. Institutional review board practices regarding assent in pediatric research. Pediatrics. 2004;113 :1747 –1752[Abstract/Free Full Text]
11. McWilliams R, Hoover-Fong J, Hamosh A, Beck S, Beaty T, Cutting G. Problematic variation in local institutional review of a multicenter genetic epidemiology study. JAMA. 2003;290 :360 –366[Abstract/Free Full Text]
12. Stair TO, Reed CR, Radeos MS, Koski G, Camargo CA. Variation in institutional review board responses to a standard protocol for a multicenter clinical trial. Acad Emerg Med. 2001;8 :636 –641[ISI][Medline]
13. Weise KL, Smith ML, Maschke KJ, Copeland HL. National practices regarding payment to research subjects for participating in pediatric research. Pediatrics. 2002;110 :577 –582[Abstract/Free Full Text]
14. Dickert N, Grady C. What's the price of a research subject? Approaches to payment for research participation. N Engl J Med. 1999;341 :198 –203[Free Full Text]
15. Wendler D, Rackoff JE, Emanuel EJ, Grady C. The ethics of paying for children's participation in research. J Pediatr. 2002;141 :166 –171[CrossRef][ISI][Medline]
16. Field MJ, Behrman RE, Institute of Medicine (US). Committee on Clinical Research Involving Children. Ethical conduct of clinical research involving children. Washington, DC: National Academies Press; 2004

This article has been cited by other articles:

				P. L. Williams, R. Van Dyke, M. Eagle, D. Smith, C. Vincent, G. Ciupak, J. Oleske, G. R. Seage III, and for the PACTG 219C Team Association of Site-specific and Participant-specific Factors with Retention of Children in a Long-term Pediatric HIV Cohort Study Am. J. Epidemiol., June 1, 2008; 167(11): 1375 - 1386. [Abstract] [Full Text] [PDF]

				S. L. Berg Ethical Challenges in Cancer Research in Children Oncologist, November 1, 2007; 12(11): 1336 - 1343. [Abstract] [Full Text] [PDF]

				A. R. Tait, T. Voepel-Lewis, and S. Malviya Presenting Research Information to Children: A Tale of Two Methods Anesth. Analg., August 1, 2007; 105(2): 358 - 364. [Abstract] [Full Text] [PDF]

				A. A. Kon Assent in Pediatric Research Pediatrics, May 1, 2006; 117(5): 1806 - 1810. [Full Text] [PDF]

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Kimberly, M. B. Articles by Schreiner, M. Search for Related Content PubMed Articles by Kimberly, M. B. Articles by Schreiner, M. Related Collections Office Practice

	Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 2006 American Academy of Pediatrics. All rights reserved.